Pyrazinamide triggers degradation of its target aspartate decarboxylase

Nat Commun. 2020 Apr 3;11(1):1661. doi: 10.1038/s41467-020-15516-1.


Pyrazinamide is a sterilizing first-line tuberculosis drug. Genetic, metabolomic and biophysical analyses previously demonstrated that pyrazinoic acid, the bioactive form of the prodrug pyrazinamide (PZA), interrupts biosynthesis of coenzyme A in Mycobacterium tuberculosis by binding to aspartate decarboxylase PanD. While most drugs act by inhibiting protein function upon target binding, we find here that pyrazinoic acid is only a weak enzyme inhibitor. We show that binding of pyrazinoic acid to PanD triggers degradation of the protein by the caseinolytic protease ClpC1-ClpP. Thus, the old tuberculosis drug pyrazinamide exerts antibacterial activity by acting as a target degrader, a mechanism of action that has recently emerged as a successful strategy in drug discovery across disease indications. Our findings provide the basis for the rational discovery of next generation PZA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / pharmacology*
  • Antitubercular Agents / therapeutic use
  • Bacterial Proteins / metabolism
  • Carboxy-Lyases / antagonists & inhibitors*
  • Carboxy-Lyases / genetics
  • Carboxy-Lyases / metabolism
  • Drug Resistance, Bacterial / genetics
  • Endopeptidase Clp / metabolism
  • Heat-Shock Proteins / metabolism
  • Humans
  • Microbial Sensitivity Tests
  • Mutation
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology
  • Mycobacterium tuberculosis / genetics
  • Proteolysis / drug effects*
  • Pyrazinamide / analogs & derivatives*
  • Pyrazinamide / pharmacology
  • Pyrazinamide / therapeutic use
  • Tuberculosis / drug therapy
  • Tuberculosis / microbiology


  • Antitubercular Agents
  • Bacterial Proteins
  • ClpC1 protein, Mycobacterium tuberculosis
  • Heat-Shock Proteins
  • Pyrazinamide
  • pyrazinoic acid
  • Endopeptidase Clp
  • Carboxy-Lyases
  • aspartate 4-decarboxylase